Low density lipoprotein quality and discordance with apolipoprotein B in intensively controlled Type 1 diabetes: Any relationship with nutrition?

Type 1 diabetes (T1D) is partly characterised by a higher prevalence of cardiovascular disease (CVD). Despite low density lipoprotein cholesterol (LDL-C) being a commonly treated target, apolipoprotein B (Apo B) has been shown to be a superior predictor of CVD and discordance between these two markers may predispose patients to altered risk(1). The distribution of LDL-C also contributes to these risks, with LDL III & IV fractions possessing greater atherogenic potential(2). Few studies have investigated LDL-C quality and its discordance with Apo B in relation to the nutritional intake of patients with intensively controlled Type 1 diabetes. The aim of this study was to address this dearth of research. Following ethical approval and informed consent 28 patients (32 % male; 68 % female) (mean age 48 ± 15) were asked to complete a food frequency questionnaire (FFQ), donate a sample of blood and allow the authors access to their medical records to determine HbA1c. The initial FFQ responses were processed using FETA software. The blood sample was analysed for LDL-C, constituent subfractions and Apo B. All data were interrogated using descriptive statistics. Dichotomous dependent variables pertaining to LDL-C and Apo B were compared using McNemar’s test and correlations between dietary variables were determined with Spearman’s rho test. Significant differences were shown between LDL-C categories when compared to Apo B (p = 0·039) and the majority of patients (46·4 %) presented LDL-C >2·0 mmol/L and Apo B >80 mg/dL (Fig. 1). Although not discordant, these findings still suggest an increased risk according to recommendations(3). Closer inspection of results revealed that individuals with raised LDL-C typically had an abundance of LDL I & II fractions which may somewhat reduce this risk (Fig. 2). Spearman’s correlation applied to the whole population produced no relationship between diet and LDL-C or Apo B; however, when focussing on the predominant ‘at risk’ cluster significant and strong relationships between LDL-C and total carbohydrate (R2 = 0·835; p = <0·001) and sucrose (R2 = 0·758; p = 0·003) were found. No hypoglycaemia data were collected and the authors tentatively speculate that these relationships may be a consequence of its treatment. In the light of the small sample size a further more comprehensive investigation with an appropriately powered sample would be beneficial

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

YesTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes

An investigation into the eating behaviours of adult patients with Type 1 diabetes using continuous subcutaneous insulin infusion therapy compared to those using multiple daily injections

Multiple daily injections (MDI) are an intensive method of administering an external source of basal and bolus insulin for patients with Type 1 diabetes (T1D). This therapy requires 4-5 injections per day, is regarded as an effective method of achieving glycaemic control and is commonly used. If HbA1c remains above 8.5% or if a patient is experiencing disabling hypoglycaemic episodes continuous subcutaneous insulin infusion (CSII) therapy may be recommended1. CSII provides flexible insulin administration via a small, electronic pump unit and has been associated with various benefits when compared to MDI, including increased glycaemic control, reduced occurrence of hypoglycaemia and improvements in the dawn phenomenon1,2. Furthermore, the flexible nature of CSII potentially allows patients to enjoy a liberalised diet compared to those using the relatively structured MDI regime2. There is a dearth of evidence focussing on the eating behaviours of these patients and research into this area would be useful to inform both treatment and the evaluation of risk. Following ethical approval and informed consent patients with T1D using either CSII or MDI from the Royal Liverpool Hospital were asked to complete an EPIC-Norfolk food frequency questionnaire (FFQ). Responses were processed using FETA software and demographic data from participants’ medical records were added. All data were initially analysed using descriptive statistics. Any data not normally distributed were transformed logarithmically and t-tests and Mann-Whitney-U-tests were then carried out. The study population consisted of 60 patients (33.3% male, 66.7% female) with 40 using CSII and 20 using MDI and a mean age of 48±16 years. The majority of patients were overweight or obese (71.4% CSII, 57.1% MDI), however energy intake was below the reference nutrient intake (RNI) for both CSII and MDI groups. Patients using both CSII and MDI consumed protein above the RNI for males and females3. Despite this protein contributed towards 18.6% of the daily energy intake of patients using CSII and 19.0% of those using MDI. Total carbohydrate (CHO) consumption was below the RNI of 50%, however it should be noted that consumption of total sugars was above the RNI for males and females in both groups. This may be partly explained by the consumption of fruit which was also higher in those using CSII. Total fat and saturated fat consumption was marginally above the RNI’s. There were no statistically significant associations between any variables and the diets of the two populations appear largely homogenous, despite slight deviations of some nutrients from RNI’s. Further analysis of total energy, protein and CHO quality is warranted

The influence of continuous subcutaneous insulin infusion therapy vs. multiple daily injections upon the diet of those with Type 1 diabetes: A food diary investigation

There exist a number of therapeutic options for the management of Type 1 diabetes (T1D). Multiple daily injections (MDI) are one such treatment and involve 4-5 daily subcutaneous injections of insulin. This frequently used approach is widely regarded as an effective method of controlling glycaemia; however, if a patient continues to suffer disabling episodes of hypoglycaemia, or if HbA1c remains above 8.5% continuous subcutaneous insulin infusion (CSII) may instead be recommended1. This therapy employs a small programmable pump device to facilitate the administration of insulin to the patient via a cannula. Various advantages of CSII have been documented compared to MDI, including improvements in glycaemic control and reduced incidence of both hypoglycaemia and the dawn phenomenon. An additional attribute, characterised by the flexible nature of the therapy, is that a liberalised diet may be enjoyed by patients, which in turn may infer potential nutrition and quality of life aberrations. This phenomenon is surprisingly under researched and further investigations to inform both treatment and risk would therefore be beneficial. Following ethical approval and informed consent patients with T1D using either CSII or MDI from the Royal Liverpool Hospital were asked to complete a 5 day weighed food diary. Dietplan 6 software was used to process the responses and demographic data from participants’ medical records were added to the dataset. All data were then interrogated using descriptive statistics and any non-normal data were transformed logarithmically before further enquiry with t-tests or analysed non-parametrically with Mann-Whitney-U-tests. The sample comprised of 20 patients (35% male, 65% female) with 11 using CSII and 9 using MDI. The patients’ mean age was 49±16 years and the majority were overweight or obese (72.7% CSII, 55.6% MDI). Nutrient Amount per day (CSII group) Amount per day (MDI group) % energy intake per day (CSII group) % energy intake per day (MDI group) Energy 1866.6 Kcal 2110.5 Kcal N/A N/A Protein 69.0 g/day 89.9 g/day 14.8 17.0 Total CHO 232.3 g/day 251.8 g/day 46.7 44.7 Total sugars 99.8 g/day 88.6 g/day 20.0 15.7 Total fat 73.5 g/day 80.1 g/day 35.4 34.2 Saturated fat 31.6 g/day 29.8 g/day 15.2 12.7 Table. Selected food diary results from patients using CSII and MDI compared to reference nutrient intakes. Results showed mean energy intake was below the reference nutrient intake (RNI) for the CSII group; potentially suggestive of underreporting (Table)3. Patients using both CSII and MDI consumed protein above the RNI; however, this macronutrient contributed towards 14.8% of the daily energy intake of patients using CSII and 17.0% of those using MDI3. Total carbohydrate (CHO) consumption was below the RNI of 50%; however, it should be noted that consumption of total sugars was above the RNI for males and females in both groups4. Previous research by the authors suggesting habitual fruit consumption, particularly in those using CSII, may explain this5. Total fat and saturated fat consumption was mostly synonymic with RNI’s. Although no statistically significant associations were seen between any of the variables and the diets of the two populations appeared largely homogenous it is reassuring that no detrimental changes occurred. Despite this further analysis of total energy, protein and CHO quality is warranted

The serum proteome of Atlantic salmon, Salmo salar, during pancreas disease (PD) following infection with salmonid alphavirus subtype 3 (SAV3)

Salmonid alphavirus is the aetological agent of pancreas disease (PD) in marine Atlantic salmon, Salmo salar, and rainbow trout, Oncorhynchus mykiss, with most outbreaks in Norway caused by SAV subtype 3 (SAV3). This atypical alphavirus is transmitted horizontally causing a significant economic impact on the aquaculture industry. This histopathological and proteomic study, using an established cohabitational experimental model, investigated the correlation between tissue damage during PD and a number of serum proteins associated with these pathologies in Atlantic salmon. The proteins were identified by two-dimensional electrophoresis, trypsin digest and peptide MS/MS fingerprinting. A number of humoral components of immunity which may act as biomarkers of the disease were also identified. For example, creatine kinase, enolase and malate dehydrogenase serum concentrations were shown to correlate with pathology during PD. In contrast, hemopexin, transferrin, and apolipoprotein, amongst others, altered during later stages of the disease and did not correlate with tissue pathologies. This approach has given new insight into not only PD but also fish disease as a whole, by characterisation of the protein response to infection, through pathological processes to tissue recovery. Biological significance: Salmonid alphavirus causes pancreas disease (PD) in Atlantic salmon, Salmo salar, and has a major economic impact on the aquaculture industry. A proteomic investigation of the change to the serum proteome during PD has been made with an established experimental model of the disease. Serum proteins were identified by two-dimensional electrophoresis, trypsin digest and peptide MS/MS fingerprinting with 72 protein spots being shown to alter significantly over the 12 week period of the infection. The concentrations of certain proteins in serum such as creatine kinase, enolase and malate dehydrogenase were shown to correlate with tissue pathology while other proteins such as hemopexin, transferrin, and apolipoprotein, altered in concentration during later stages of the disease and did not correlate with tissue pathologies. The protein response to infection may be used to monitor disease progression and enhance understanding of the pathology of PD

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions

Exploiting separability in large-scale linear support vector machine training

Linear support vector machine training can be represented as a large quadratic program. We present an efficient and numerically stable algorithm for this problem using interior point methods, which requires only O(n) operations per iteration. Through exploiting the separability of the Hessian, we provide a unified approach, from an optimization perspective, to 1-norm classification, 2-norm classification, universum classification, ordinal regression and ɛ-insensitive regression. Our approach has the added advantage of obtaining the hyperplane weights and bias directly from the solver. Numerical experiments indicate that, in contrast to existing methods, the algorithm is largely unaffected by noisy data, and they show training times for our implementation are consistent and highly competitive. We discuss the effect of using multiple correctors, and monitoring the angle of the normal to the hyperplane to determine termination